Advances in molecular imaging are yielding a new generation of single-photon-emission-computed- tomography (SPECT) brain-imaging agents that will lead the way in understanding the human brain by enabling the development of biomarkers with unprecedented specificity for mapping neuroreceptors and proteinopathies associated with disease and dementia. SPECT is an ideal tracer-imaging tool for investigating the underlying mechanisms in brain disorders, their differential diagnoses, and monitoring their treatment because of its lower cost and radiation dose relative to PET, longer half-lives of the radionuclides imaged, and ability to simultaneously image multiple imaging agents labeled with different radionuclides. However, most clinical brain SPECT is still being performed by 2-headed systems with collimators designed for planar scintigraphy. To meet the potential for better patient care offered by these new imaging agents, and vastly improve the utility of existing agents, a revolution in SPECT brain-imaging system design is required. In Phase 1 of this Biomedical Research Partnership (BRP) application we propose to meet this requirement by creating a multi-detector-module multi-pinhole (MPH) SPECT brain-imaging system ideally suited for quantitative dynamic and high-spatial-resolution static SPECT imaging. Based on its heritage and intent for clinical imaging, we have named this proposed system AdaptiSPECT-C. Dynamic imaging will be enabled by obtaining sufficient angular sampling without the need for rotation. The system will automatically adapt its imaging characteristics (aperture size and number of pinholes open for imaging) in response to the imaging tasks and individual patients. It will thereby optimize lesion detection and quantification, as well as provide optimal data for pharmacokinetic analysis within structures throughout the brain. Automatic alignment to existent CT diagnostic studies of the patient for use in providing anatomical correlation, formation of attenuation maps, and templates for PVE correction will be enabled through usage of depth- sensing cameras, which will also be used for correction for head motion. Comparison of AdaptiSPECT-C to clinical systems will be conducted through inviCRO, one of the nation's top contract research organizations (CROs) serving the pharmaceutical industry. These studies will provide the documentation of system performance necessary to enable ?Big-Pharma? companies to use the system to gather the clinical data necessary for FDA approval of new pharmaceuticals. Our Specific Aims are: 1. Construct an adaptable brain-SPECT system and test performance versus design specifications; 2. Develop reconstruction software for optimal image quality and activity quantification; 3.Integrate depth-sensing camera imaging to correct patient motion and align existent CT slices; and 4. Incorporate analysis software, and validate system through prototype human imaging.